How do you treat a rare obesity disorder that defies diet and exercise?

Ashley H. Shoemaker, MD, Assistant Professor of Pediatric Endocrinology and Diabetes, Vanderbilt University Medical Center

What if your brain couldn’t register the meals you ate or, despite restricting food intake, you continued to gain weight? For people with hypothalamic obesity (HO), there are no approved treatment options to help with this rare, incurable condition that causes uncontrollable weight gain. Often, people with HO also bear an increased risk of obesity-related morbidity and mortality due to conditions such as type 2 diabetes, non-alcoholic fatty liver disease, high blood pressure, and cardiovascular disease.

HO is a disorder caused by injury to the hypothalamus, the region of the brain responsible for regulating sleep, body temperature, and hunger. The most common cause of damage to the hypothalamus is injury sustained during surgery or treatment for rare noncancerous brain tumors — the most common is craniopharyngioma (CP), which occurs in about 1.6 per million people — but can also result from direct tissue damage from CP, other types of brain surgery, or head trauma. CP occurs most frequently in children ages 5 to 15 years and adults 45 to 60 years of age, which is reflected in the HO patient population. Once injured, the hypothalamus becomes ineffective at communicating between the nervous and endocrine systems, leading to rapid, excessive accumulation of body weight that persists even under a restricted diet and increased physical activity.

Hypothalamic obesity is complicated

The hypothalamus is made up of a number of subregions, known as nuclei, that play specific roles in homeostasis by regulating everything from heart rate to processing fear to dilation of the pupils. The effects of an injury to this part of the brain vary widely depending on the nuclei that are damaged. As such, the symptoms of HO also vary widely and often go beyond loss of feeling satiated to include memory impairment, attention deficit, extreme fatigue or loss of natural sleep cycles, issues with impulse control and decreased energy.

There are currently no medications approved for HO. To date, treatments have primarily centered around approaches for general obesity, sleep disorders, hormone and metabolic regulation, and hyperinsulinism, but these are often ineffective for the long term and are accompanied by significant side effects. The lack of targeted therapeutics for HO is compounded by a lack of knowledge around this disease and the variability between patients.

Targeted, personalized treatments are needed

For a disease as complicated and misunderstood as HO, there is a need to look at it not as a list of symptoms to be controlled using existing medications, but by exploring and developing novel therapeutics that can compensate for the damage to the hypothalamus and facilitate new integration of signaling throughout the body.

Several ongoing clinical trials include medications designed to help control appetite, reduce food cravings, and increase metabolic rate that have shown promise, but more clinical research is needed to determine the efficacy and safety of these medicines. Given the various ways HO can impact individuals, it is increasingly important to raise awareness across the healthcare continuum about the disease and clinical trials that may lead to a better understanding of how to improve treatment options for people with HO. While it is unlikely that a single therapeutic could address all the complications associated with this condition, or be effective for all patients with HO, clinical trials are the best path to finding treatments options that offer hope to patients and their families.

Continued research is also needed to understand how treatments can be further personalized for each patient, how to identify and compensate for variations among patients, and, most importantly, how to improve surgical techniques and treatment of CP and brain trauma to avoid the onset of HO altogether. May is Brain Tumor Awareness Month and it’s important for the healthcare community to raise awareness of lesser-known rare diseases such as HO, find ways to deepen our understanding of underlying pathophysiology, and take coordinated steps to improve the lives of people who have limited effective treatment options.

Learn more about hypothalamic obesity here.